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Nutraceuticals Derived From Pomegranate Selectively Enhance Vitamin D Receptor Signaling to Amplify Key Vitamin D Target Genes
Author(s) -
Livingston Sarah,
Lucas Daniel,
Sabir Marya S.,
Mallick Sanchita,
Purdin Hespera,
Nidamanuri Sree,
Whitfield G. Kerr,
Haussler Carol A.,
Haussler Mark R.,
Jurutka Peter W.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.09440
Subject(s) - calcitriol receptor , chemistry , nuclear receptor , vitamin d and neurology , receptor , retinoid x receptor , signal transduction , pharmacology , biochemistry , transcription factor , microbiology and biotechnology , biology , endocrinology , gene
The active vitamin D hormone, 1,25‐dihydroxyvitamin D (1,25D), mediates its biological effects by binding to the nuclear vitamin D receptor (VDR) and promoting heterodimerization with retinoid X receptors (RXRs). Various nutraceuticals, including resveratrol and curcumin, have been postulated to interact with the vitamin D signaling pathway. More recently, health benefits attributed to pomegranate have been associated with its high content of polyphenols, specifically ellagitannins, which are metabolized by the gut microbiota to produce Urolithin A (UA). In this study, we investigated the ability of UA to modulate 1,25D signaling via transcription and qPCR assays. We hypothesized that 1,25D in combination with urolithin will stimulate VDR activity more than 1,25D alone, increasing transcription of 1,25D target genes. The increased activation of anti‐oxidation genes by 1,25D and UA could help combat reactive oxygen species and attenuate cellular “aging”. Our results indicate that there is a significant increase in VDR transcriptional activity when HEK‐293 kidney cells are treated with UA in conjunction with 1,25D at several 1,25D and UA concentrations. A similar effect was also observed using three structurally‐distinct 1,25D response elements. The potentiation of VDR activity via UA retains receptor‐selectivity since UA did not promote further activation of other receptor‐ligand complexes including estrogen‐ER, rexinoid‐RXR and TO‐LXR. Finally, amplification of serotonin production in brain cells was greatest with a combined cocktail of 1,25D/UA/resveratrol via qPCR (TPH2 gene) and ELISA (5‐HT). In order to probe the molecular mechanism of UA amplification in VDR activity, we tested VDR‐RXR heterodimerization and observed no effect of UA. However, UA activates AMP‐kinase, and we found potential AMP kinase phosphorylation consensus sites in the VDR protein sequence. Collectively, our novel results position gut microbiota‐derived UA as a putative VDR modulator, suggesting that the influences of 1,25D and UA converging on VDR may potentially mediate anti‐aging and promote longevity. Support or Funding Information Financial support/grant sponsor: National Institutes of Health; grant numbers: DK033351 and CA140285